1. Field of Invention
The present invention relates to a method for the production of porous particles and, more particularly, to a method for the production of porous particles including a therapeutic constituent that can be effectively dosed to humans via inhalation.
2. Description of Related Art
Respiratory drug delivery (“RDD”) therapy has been used for the treatment of various pulmonary disorders such as, for example, cystic fibrosis, bronchial infections, pneumonia and sinusitis. The delivery of drugs and other therapeutic constituents through the lungs allows for direct adsorption of macromolecules and small doses of hydrophobic drugs into the blood stream through the large alveolar surface and thin epithelial lining. The bioavailability of these molecules has been observed to be higher when delivered through the lungs as compared to other non-invasive delivery routes.
Although the administration of drugs via RDD is highly desirable, it has proven to be quite difficult to process some drugs into particles adequate for inhalation. One of the primary challenges includes modulation of the release of the drug(s) from the inhaled particles while simultaneously avoiding the rapid natural clearance of inhaled particles from the lungs. These challenges can be overcome by incorporating the drug in a matrix material in the form of low bulk density porous particles that have a geometric diameter within the range of from about 10 μm to about 20 μm and an equivalent aerodynamic diameter within the range of from about 1 μm to about 5 μm. Particles having these characteristics are not eliminated by alveolar microphage clearance due to their large geometric size, enabling the drug to be used for sustained release applications in the lungs. In vitro studies of large, porous particles consisting of deslorelin, a peptide drug, in a poly-lactic-glycolic acid (“PLGA”) matrix material indicated that the uptake of deslorelin into respiratory epithelial cells (Calu-3 and A549) and rat alveolar macrophages was decreased by 87%, 91%, and 50% respectively, compared to conventional small non-porous particles, suggesting the ability of these particles to avoid macrophage uptake and sustain lung delivery. See Koushik, K. and Kompella, U. B., Preparation of large porous deslorelin-PLGA microparticles with reduced residual solvent and cellular uptake using a supercritical CO2 process, Pharm Res. 21:524-535 (2004).
The conventional methods of precipitating porous composite drug/matrix material particles include spray drying, evaporating or extracting solvents from emulsions, spray freezing into liquid nitrogen and supercritical fluid precipitation. Spray drying methods are generally not suitable for thermally labile materials due to the elevated temperatures involved in processing. Some emulsion-based techniques have had problems with residual solvent in the final product and the processing time for precipitating particles by evaporating a solvent from an emulsion is prohibitively long in most cases. The spray freezing technique is not suitable for processing compounds such as proteins that can be damaged due to temperature stresses.